Complement, activity, pathway

Figure 15.1 Complement activation pathways. The classical, lectin and alternative pathways converge into a final common pathway when C3 convertase (C3 con) cleaves C3 into C3a and C3b. Ab = antibody, Ag = antigen, Cl-INH = Cl inhibitor, MAC = membrane attack complex, MASP = MBL-associated serine protease, MBL = mannose-binding lectin, P = properdin. Overbar indicates activation.

Leinhase I, Rozanski M, Harhausen D, Thurman JM, Schmidt 01, Hossini AM, Taha ME, Rittirsch D, Ward PA, Holers VM, Ertel W, Stahel PF (2007) Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody a randomized placebo-controlled study in mice. J Neuroinflammation 4 13... 

Arabinofuranosides were removed from PVa, which resulted in an increase in the activity this was in contrast to the findings of Kiyohara et al. [35] who foimd no change in activity after removal of similar units from A. acutiloba pectin. For this polymer it was suggested that the minimum requirement for complement activation via the classical pathway was j6-l,6-linked galactan attached to the rhamnogalacturonan backbone, which also appears to be an important part of the backbone for PVa. 

The alternative pathway may become activated by lipopolysaccharides, endotoxin (sepsis), virus, fungi, immunoglobulin A-antigen (IgA-Ag) immunocom-plexes, and foreign material. These activate C3, after which the common pathway of complement activation takes place (Fig. 4). There are also a number of inhibitors that regulate and control complement activation. The most important are the Cl-esterase inhibitor (Cl-Inh) and the membrane attack complex inhibitor factor (MACIF CD59). In sepsis a relative deficiency of Cl-Inh has been reported. Administration of Cl-Inh to patients with septic shock attenuates complement acti-... 

Fig. 4. The classical and alternative pathway cascade of complement activation. activation Cl-inh., Cl-esterase inhibitor MACIF, membrane attack complex inhibiting factor (—CD59).

During complement activation via the classical pathway, nine major complement components (designated C1-C9) become activated in a sequential process, the product of each activation step being an enzyme that catalyses a subsequent step in the cascade. The purpose of the cascade is twofold firstly, a sequential activation process decreases the possibility of nonspecific activation secondly, the initial response is amplified so that large numbers of complement molecules become activated in response to small amounts of initial signal. The order of events is as follows. 

Figure 1.14. Complement activation via the classical pathway. The sequential activation of complement following antibody deposition onto a surface is shown. C9 forms a pore in the membrane, eventually leading to cell death by osmotic lysis. See text for details.

Figure 1.15. Complement activation via the alternative pathway. Always present in serum are trace amounts of C3b, which may attach to recognition sites on, for example, yeast cell walls. C3b may combine with serum factor B to form C3bB, and this complex is acted upon by factor D to form C3bBb. This latter complex is a C3 convertase and may act upon C3 to form more C3b to amplify the process. The C3bBb-coated particles may activate other complement components (C4-C9) or be recognised by complement receptors on neutrophils.

Complement A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed components of complement and are designated by the symbols... 

Cotton dust activates complement vitro by both the classical (antibody dependent) and alternative (antibody independent) pathways (12,47,48). It is proposed that endotoxins may be the agents responsible for complement activation (49). Cotton dust extractions maximizing endotoxin content are 10 times more potent than other extracts in activating complement (12). Activation of complement via the alternative pathway has also been... 

In vitro studies indicate that cotton mill dust extracts do activate complement by the alternative pathway. Kutz et al. (36) proposed that endotoxin is not the only agent responsible for complement activation, as microgram rather than nanogram quantities of purified endotoxin are required to induce the degree of complement activation observed with crude cotton dust extract. Several investigators (36, 37) have thus proposed endotoxin... 

Murthy, K. H., et al. (2001). Crystal structure of a complement control protein that regulates both pathways of complement activation and binds heparan sulfate proteoglycans. Cell 104,301-311. 

Complement classical pathway inhibition. Ethyl acetate and methanol extracts of the fresh leaf were active on red blood cells, IC50 greater than 7.7 pg/mL and greater than 5.8 pg/mL, respectively " ". Cyclo-oxygenase inhibition. Essential oil of the unripe fruit, at a concentration of 100 pg/mL, produced weak activity on platelets " . 

FIGURE 6.9 The classical pathway of complement activation is initiated by binding of Clq to antibody on a surface such as a bacterial surface. Multiple molecules of IgG bound on the surface of a pathogen allow the binding of a single molecule of Clq to two or more Fc pieces. The binding of Clq activates the associated Clr, which becomes an active enzyme that cleaves the proenzyme Cls, generating a serine protease that initiates the classical complement cascade. 

The complement system is a humoral effector of inflammation which is activated by a cascade mechanism through the classical and/or alternative pathway [62]. Activation of the system is normally beneficial for the host. However, excessive activation may evoke pathological reaction in a variety of immunological and degenerative diseases and hyperacute rejection in transplantation. Therefore, the modulation of complement activity should be useful in the therapy of inflammatory diseases. 

The principal stages in complement activation. Complement activation occurs exclusively on the microbial cell membrane, where it is triggered by bound antibody or microbial envelope polysaccharides, both of which activate early complement components. Two sets of early components belong to two distinct pathways of complement activation. Activation of each complement system involves a cascade of proteolytic reactions. Each component of the complement system is a proenzyme that is activated by the preceding component of the chain by a limited proteolytic cleavage. The ultimate result of this chain reaction is the development of a complex that attacks the cell membrane. 

---